Pharmacogenetic‐guided dosing for fluoropyrimidine (DPYD) and irinotecan (UGT1A1*28) chemotherapies for patients with cancer (PACIFIC‐PGx): A multicenter clinical trial
Abstract PACIFIC‐PGx evaluated the feasibility of implementing pharmacogenetics (PGx) screening in Australia and the impact of DPYD/UGT1A1 genotype‐guided dosing on severe fluoropyrimidine (FP) and irinotecan‐related toxicities and hospitalizations, compared to historical controls. This prospective...
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| Format: | Article |
| Language: | English |
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Wiley
2024-12-01
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| Series: | Clinical and Translational Science |
| Online Access: | https://doi.org/10.1111/cts.70083 |
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| author | Sarah Glewis Senthil Lingaratnam Benjamin Lee Ian Campbell Maarten IJzerman Mussab Fagery Sam Harris Chloe Georgiou Craig Underhill Mark Warren Robert Campbell Madawa Jayawardana S. Sandun M. Silva Jennifer H. Martin Jeanne Tie Marliese Alexander Michael Michael |
| author_facet | Sarah Glewis Senthil Lingaratnam Benjamin Lee Ian Campbell Maarten IJzerman Mussab Fagery Sam Harris Chloe Georgiou Craig Underhill Mark Warren Robert Campbell Madawa Jayawardana S. Sandun M. Silva Jennifer H. Martin Jeanne Tie Marliese Alexander Michael Michael |
| author_sort | Sarah Glewis |
| collection | DOAJ |
| description | Abstract PACIFIC‐PGx evaluated the feasibility of implementing pharmacogenetics (PGx) screening in Australia and the impact of DPYD/UGT1A1 genotype‐guided dosing on severe fluoropyrimidine (FP) and irinotecan‐related toxicities and hospitalizations, compared to historical controls. This prospective single arm trial enrolled patients starting FP/irinotecan for any cancer between 7 January 2021 and 25 February 2022 from four Australian hospitals (one metropolitan, three regional). During the accrual period, 462/487 (95%) consecutive patients screened for eligibility for DPYD and 50/109 (46%) for UGT1A1 were enrolled and genotyped (feasibility analysis), with 276/462 (60%) for DPYD and 30/50 (60%) for UGT1A1 received FP/irinotecan (safety analysis). DPYD genotyping identified 96% (n = 443/462) Wild‐Type, 4% (n = 19/462) Intermediate Metabolizers (50% dose reduction), and 0% Poor Metabolizers. UGT1A1 genotyping identified 52% (n = 26/50) Wild‐Type, 40% (n = 20/50) heterozygous, and 8% (n = 4/50) homozygous (30% dose reduction). Key demographics for the FP/irinotecan safety cohorts included: age range 23–89/34–74 years, male 56%/73%, Caucasian 83%/73%, lower gastrointestinal cancer 50%/57%. Genotype results were reported prior to cycle‐1 (96%), average 5–7 days from sample collection. PGx‐dosing for DPYD variant allele carriers reduced high‐grade toxicities compared to historic controls (7% vs. 39%; OR = 0.11, 95% CI 0.01–0.97, p = 0.024). High‐grade toxicities among Wild‐Type were similar (14% vs. 14%; OR = 0.99, 95% CI 0.64–1.54, p = 0.490). PGx‐dosing reduced FP‐related hospitalizations (−22%) and deaths (−3.7%) compared to controls. There were no high‐grade toxicities or hospitalizations for UGT1A1*28 homozygotes. PGx screening and prescribing were feasible in routine oncology care and improved patient outcomes. Findings may inform expanded PGx programs within cancer and other disease settings. |
| format | Article |
| id | doaj-art-315f8f44bbf94054b8b0bd32562fa91f |
| institution | Kabale University |
| issn | 1752-8054 1752-8062 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Wiley |
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| series | Clinical and Translational Science |
| spelling | doaj-art-315f8f44bbf94054b8b0bd32562fa91f2024-12-24T15:26:30ZengWileyClinical and Translational Science1752-80541752-80622024-12-011712n/an/a10.1111/cts.70083Pharmacogenetic‐guided dosing for fluoropyrimidine (DPYD) and irinotecan (UGT1A1*28) chemotherapies for patients with cancer (PACIFIC‐PGx): A multicenter clinical trialSarah Glewis0Senthil Lingaratnam1Benjamin Lee2Ian Campbell3Maarten IJzerman4Mussab Fagery5Sam Harris6Chloe Georgiou7Craig Underhill8Mark Warren9Robert Campbell10Madawa Jayawardana11S. Sandun M. Silva12Jennifer H. Martin13Jeanne Tie14Marliese Alexander15Michael Michael16Department of Pharmacy Peter MacCallum Cancer Centre Melbourne Victoria AustraliaDepartment of Pharmacy Peter MacCallum Cancer Centre Melbourne Victoria AustraliaDepartment of Pharmacy Peter MacCallum Cancer Centre Melbourne Victoria AustraliaSir Peter MacCallum Department of Oncology University of Melbourne Parkville Victoria AustraliaSir Peter MacCallum Department of Oncology University of Melbourne Parkville Victoria AustraliaCancer Health Services Research Unit, Centre for Cancer Research, Faculty of Medicine, Dentistry and Health Sciences University of Melbourne Parkville Victoria AustraliaDepartment of Medical Oncology Bendigo Health Bendigo Victoria AustraliaDepartment of Medical Oncology Bendigo Health Bendigo Victoria AustraliaVCCC Alliance Parkville Victoria AustraliaDepartment of Medical Oncology Bendigo Health Bendigo Victoria AustraliaDepartment of Medical Oncology Bendigo Health Bendigo Victoria AustraliaSir Peter MacCallum Department of Oncology University of Melbourne Parkville Victoria AustraliaCentre for Health Systems and Safety Research, Australian Institute of Health Innovation Macquarie University Macquarie Park New South Wales AustraliaSchool of Medicine and Public Health University of Newcastle Callaghan New South Wales AustraliaSir Peter MacCallum Department of Oncology University of Melbourne Parkville Victoria AustraliaDepartment of Pharmacy Peter MacCallum Cancer Centre Melbourne Victoria AustraliaSir Peter MacCallum Department of Oncology University of Melbourne Parkville Victoria AustraliaAbstract PACIFIC‐PGx evaluated the feasibility of implementing pharmacogenetics (PGx) screening in Australia and the impact of DPYD/UGT1A1 genotype‐guided dosing on severe fluoropyrimidine (FP) and irinotecan‐related toxicities and hospitalizations, compared to historical controls. This prospective single arm trial enrolled patients starting FP/irinotecan for any cancer between 7 January 2021 and 25 February 2022 from four Australian hospitals (one metropolitan, three regional). During the accrual period, 462/487 (95%) consecutive patients screened for eligibility for DPYD and 50/109 (46%) for UGT1A1 were enrolled and genotyped (feasibility analysis), with 276/462 (60%) for DPYD and 30/50 (60%) for UGT1A1 received FP/irinotecan (safety analysis). DPYD genotyping identified 96% (n = 443/462) Wild‐Type, 4% (n = 19/462) Intermediate Metabolizers (50% dose reduction), and 0% Poor Metabolizers. UGT1A1 genotyping identified 52% (n = 26/50) Wild‐Type, 40% (n = 20/50) heterozygous, and 8% (n = 4/50) homozygous (30% dose reduction). Key demographics for the FP/irinotecan safety cohorts included: age range 23–89/34–74 years, male 56%/73%, Caucasian 83%/73%, lower gastrointestinal cancer 50%/57%. Genotype results were reported prior to cycle‐1 (96%), average 5–7 days from sample collection. PGx‐dosing for DPYD variant allele carriers reduced high‐grade toxicities compared to historic controls (7% vs. 39%; OR = 0.11, 95% CI 0.01–0.97, p = 0.024). High‐grade toxicities among Wild‐Type were similar (14% vs. 14%; OR = 0.99, 95% CI 0.64–1.54, p = 0.490). PGx‐dosing reduced FP‐related hospitalizations (−22%) and deaths (−3.7%) compared to controls. There were no high‐grade toxicities or hospitalizations for UGT1A1*28 homozygotes. PGx screening and prescribing were feasible in routine oncology care and improved patient outcomes. Findings may inform expanded PGx programs within cancer and other disease settings.https://doi.org/10.1111/cts.70083 |
| spellingShingle | Sarah Glewis Senthil Lingaratnam Benjamin Lee Ian Campbell Maarten IJzerman Mussab Fagery Sam Harris Chloe Georgiou Craig Underhill Mark Warren Robert Campbell Madawa Jayawardana S. Sandun M. Silva Jennifer H. Martin Jeanne Tie Marliese Alexander Michael Michael Pharmacogenetic‐guided dosing for fluoropyrimidine (DPYD) and irinotecan (UGT1A1*28) chemotherapies for patients with cancer (PACIFIC‐PGx): A multicenter clinical trial Clinical and Translational Science |
| title | Pharmacogenetic‐guided dosing for fluoropyrimidine (DPYD) and irinotecan (UGT1A1*28) chemotherapies for patients with cancer (PACIFIC‐PGx): A multicenter clinical trial |
| title_full | Pharmacogenetic‐guided dosing for fluoropyrimidine (DPYD) and irinotecan (UGT1A1*28) chemotherapies for patients with cancer (PACIFIC‐PGx): A multicenter clinical trial |
| title_fullStr | Pharmacogenetic‐guided dosing for fluoropyrimidine (DPYD) and irinotecan (UGT1A1*28) chemotherapies for patients with cancer (PACIFIC‐PGx): A multicenter clinical trial |
| title_full_unstemmed | Pharmacogenetic‐guided dosing for fluoropyrimidine (DPYD) and irinotecan (UGT1A1*28) chemotherapies for patients with cancer (PACIFIC‐PGx): A multicenter clinical trial |
| title_short | Pharmacogenetic‐guided dosing for fluoropyrimidine (DPYD) and irinotecan (UGT1A1*28) chemotherapies for patients with cancer (PACIFIC‐PGx): A multicenter clinical trial |
| title_sort | pharmacogenetic guided dosing for fluoropyrimidine dpyd and irinotecan ugt1a1 28 chemotherapies for patients with cancer pacific pgx a multicenter clinical trial |
| url | https://doi.org/10.1111/cts.70083 |
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